Transport of glutathione conjugates into secretory vesicles is mediated by the multidrug‐resistance protein 1

Luyn, Marja J. A. van; Müller, Michael; Renes, Johan; Meijer, Coby; Rj, Scheper; Nienhuis, Edith F.; Mulder, Nanno; Jansen, Petér L. M.; Vries, Elisabeth G.E. de

doi:10.1002/(sici)1097-0215(19980330)76:1<55::aid-ijc10>3.3.co;2-o

Cited by 4 publications

(5 citation statements)

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“…Significant intracellular accumulation of MRP1, possibly in the Golgi, has also been reported in the drug-selected human small cell lung carcinoma cell line GLC4-Adr (72,511). In GLC4-Adr and H69AR cells, intracellular MRP1 colocalized with vesicles that accumulated fluorescent substrates (96,511). Similarly, exposure of cells transiently transfected with MRP1 fused to green fluorescent protein (GFP) to the fluorescent anthracycline doxorubicin resulted in accumulation of drug in vesicles bounded by membranes containing the fusion protein (401).…”

Section: Fig 6 Alignment Of the Nh 2 -Terminal And Cytoplasmic Loopmentioning

confidence: 80%

“…For example, 80 -90% of MRP1 localizes to the plasma membrane in transfected HeLa and HEK293 cells (8,146,175,531) compared with only ϳ50% in multidrug resistant H69AR cells (8,72). Significant intracellular accumulation of MRP1, possibly in the Golgi, has also been reported in the drug-selected human small cell lung carcinoma cell line GLC4-Adr (72,511). In GLC4-Adr and H69AR cells, intracellular MRP1 colocalized with vesicles that accumulated fluorescent substrates (96,511).…”

Section: Fig 6 Alignment Of the Nh 2 -Terminal And Cytoplasmic Loopmentioning

confidence: 97%

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Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins

Deeley¹,

Westlake²,

Cole³

2006

Physiological Reviews

684

556

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Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the human "C" branch of the ATP binding cassette (ABC) superfamily. All C branch proteins share conserved structural features in their nucleotide binding domains (NBDs) that distinguish them from other ABC proteins. The MRPs can be further divided into two subfamilies "long" (MRP1, -2, -3, -6, and -7) and "short" (MRP4, -5, -8, -9, and -10). The short MRPs have a typical ABC transporter structure with two polytropic membrane spanning domains (MSDs) and two NBDs, while the long MRPs have an additional NH2-terminal MSD. In vitro, the MRPs can collectively confer resistance to natural product drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and, under certain circumstances, alkylating agents. The MRPs are also primary active transporters of other structurally diverse compounds, including glutathione, glucuronide, and sulfate conjugates of a large number of xeno- and endobiotics. In vivo, several MRPs are major contributors to the distribution and elimination of a wide range of both anticancer and non-anticancer drugs and metabolites. In this review, we describe what is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates. We also summarize knowledge of their possible physiological functions and evidence that they may be involved in the clinical drug resistance of various forms of cancer.

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Section: Fig 6 Alignment Of the Nh 2 -Terminal And Cytoplasmic Loopmentioning

confidence: 80%

Section: Fig 6 Alignment Of the Nh 2 -Terminal And Cytoplasmic Loopmentioning

confidence: 97%

Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins

Deeley¹,

Westlake²,

Cole³

2006

Physiological Reviews

684

556

View full text Add to dashboard Cite

show abstract

“…Although the function of MRP1 is not fully understood, it has been assumed that it acts as an exporter of xenobiotic conjugates at the basolateral membranes of cells in several tissues. In addition, the cytoplasmic localization of MRP1 suggests a role of this protein in intracellular transport of compounds, such as transport into lysosomes (Van Luyn et al. , 1998; Kaufmann et al.…”

Section: Discussionmentioning

confidence: 99%

Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse

Tydén¹,

Bjornstrom²,

Tjälve³

et al. 2010

Vet Pharm & Therapeutics

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The gene and protein expression and the cellular localization of the ABC transport proteins breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance-associated protein 2 (MRP2) have been examined in the intestines, liver and kidney in horse. High gene and protein expression of BCRP and MRP2 were found in the small intestines, with cellular localization in the apical membranes of the enterocytes. In the liver, MRP2 was present in the bile canalicular membranes of the hepatocytes, whereas BCRP was localized in the cytoplasm of hepatocytes in the peripheral parts of the liver lobuli. In the kidney both BCRP and MRP2 were predominantly present in the distal tubuli and in the loops of Henle. In most tissues, the gene and protein expression of MRP1 were much lower than for BCRP and MRP2. Immunostaining of MRP1 was detectable only in the intestines and with localization in the cytoplasm of enterocytes in the caecum and colon and in the cells of serous acini of Brunner's glands in the duodenum and the upper jejunum. The latter cells were also stained for BCRP, but not for MRP2. Many drugs used in horse are substrates for one or more of the ABC transport proteins. These transporters may therefore have important functions for oral bioavailability, distribution and excretion of substrate compounds in horse.

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“…Despite this fact, we were puzzled by the notion that a cell would purposely direct the transport of potentially toxic molecules into the lumen of the Golgi apparatus since this organelle serves important functions in protein modification and sorting . Van Luyn and co-workers have previously suggested that MRP1 functions on secretory vesicles originating from the Golgi apparatus; however, these were shown to be rapidly released from the cell. This scenario seems more reasonable since the sequestered molecules would have little time to interact with components of the intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Golgi Apparatus versus Plasma Membrane-Localized Multi-Drug Resistance-Associated Protein 1

2008

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Traditionally, proteins belonging to the ATP-binding cassette superfamily have been thought to function exclusively at the plasma membrane (PM) of cells. We have previously shown multidrug resistance-associated protein 1 (MRP1) to reside on the Golgi apparatus of the multidrug resistant (MDR) human leukemic cell line HL-60 (HL-60/ADR); however, neither the prevalence of this abnormal localization nor the functionality of the transporter at the Golgi has been thoroughly addressed. To assess the functionality of MRP1, with respect to its localization in the cell, we transfected MRP1-deficient HeLa cells with an MRP1-enhanced green fluorescent protein (MRP1-EGFP) plasmid. Untreated cells expressed MRP1-EGFP at the PM; however, cells pretreated with monensin caused the transporter to localize on the Golgi apparatus. The MRP1-mediated decline in cytosolic fluorescence of the MRP1 substrate sulforhodamine 101 (SR101) was comparatively evaluated. The rate of decline of SR101 cytosolic fluorescence was found to be of similar magnitude regardless of the localization of MRP1. Additionally, we show that a number of human leukemic cell lines appear to have an inefficient Golgi apparatus to PM secretory pathway that could be responsible for the Golgi localization of MRP1.

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Transport of glutathione conjugates into secretory vesicles is mediated by the multidrug‐resistance protein 1

Cited by 4 publications

References 0 publications

Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins

Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins

Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse

Assessment of Golgi Apparatus versus Plasma Membrane-Localized Multi-Drug Resistance-Associated Protein 1

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